Q03526 (ITK_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tyrosine-protein kinase ITK/TSK
EC=2.7.10.2

Alternative name(s):
IL-2-inducible T-cell kinase
Kinase EMT
Kinase TLK
T-cell-specific kinase

Gene names

Name:	Itk
Synonyms:	Emt, Tlk, Tsk

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	625 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Ref.14
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Subunit structure	Homooligomerizes; this association negatively regulates kinase activity. Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS By similarity. Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Ref.6 Ref.13
Subcellular location	Cytoplasm. Note: Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation By similarity.
Tissue specificity	Is detected in the thymus, lymph node and very faintly in the spleen, but is not detected in the liver, lung, kidney, heart, brain, intestine or testis. Expressed in T-lymphocytes and mast cells. It may also be expressed in natural killer cells.
Developmental stage	Is present in the fetal thymus as early as day 14 of gestation. The levels are 5- to 10-fold higher in thymocytes than in peripheral T-cells, and increase in the thymus during development from neonate to adult.
Induction	Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.
Domain	The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain contains also a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation By similarity.
Post-translational modification	Phosphorylated at Tyr-517 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-186 leads to the kinase activation. The autophosphorylated Tyr-186 lies within the substrate binding sequence of the SH3 domain By similarity.
Disruption phenotype	Mice display decreased mature thymocytes and elicit profound defect in CD4+ and CD8+ T-cell development. Additionally, they show a strong decrease of cytokine production in response to TCR receptor stimulation. Ref.5 Ref.11 Ref.12 Ref.14
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. Contains 1 Btk-type zinc finger. Contains 1 PH domain. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Biological process	Adaptive immunity Immunity
Cellular component	Cytoplasm
Domain	SH2 domain SH3 domain Zinc-finger
Ligand	ATP-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	NK T cell differentiation Inferred from mutant phenotype PubMed 18292523. Source: MGI T cell receptor signaling pathway Inferred from mutant phenotype Ref.11. Source: UniProtKB activation of phospholipase C activity Inferred from mutant phenotype Ref.11. Source: UniProtKB adaptive immune response Inferred from mutant phenotype Ref.11. Source: UniProtKB interferon-gamma production Inferred from mutant phenotype PubMed 18292523. Source: MGI interleukin-4 production Inferred from mutant phenotype PubMed 18292523. Source: MGI intracellular signal transduction Inferred from electronic annotation. Source: InterPro
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB phospholipid binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 625

625

Tyrosine-protein kinase ITK/TSK

PRO_0000088107

Regions

Domain

4 – 117

114

PH

Domain

177 – 237

61

SH3

Domain

245 – 343

99

SH2

Domain

368 – 620

253

Protein kinase

Zinc finger

119 – 155

37

Btk-type

Nucleotide binding

374 – 382

9

ATP By similarity

Sites

Active site

487

1

Proton acceptor By similarity

Metal binding

127

1

Zinc By similarity

Metal binding

138

1

Zinc By similarity

Metal binding

139

1

Zinc By similarity

Metal binding

149

1

Zinc By similarity

Binding site

396

1

ATP By similarity

Amino acid modifications

Modified residue

186

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

517

1

Phosphotyrosine; by LCK By similarity

Modified residue

570

1

Phosphoserine By similarity

Experimental info

Sequence conflict

82 – 87

6

Missing Ref.2

Sequence conflict

82 – 87

6

Missing Ref.3

Sequence conflict

82 – 87

6

Missing Ref.4

Sequence conflict

535

1

F → S in L10628. Ref.3

Sequence conflict

540

1

Y → C in L10628. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

625

Helix Strand Turn

Details...

Beta strand

178 – 180

3

Beta strand

181 – 186

6

Beta strand

200 – 202

3

Beta strand

203 – 206

4

Beta strand

211 – 214

4

Beta strand

215 – 218

4

Beta strand

220 – 222

3

Beta strand

224 – 227

4

Helix

229 – 231

3

Beta strand

232 – 234

3

Helix

240 – 242

3

Beta strand

243 – 246

4

Helix

252 – 262

11

Beta strand

268 – 272

5

Turn

275 – 277

3

Beta strand

279 – 285

7

Beta strand

290 – 292

3

Beta strand

294 – 302

9

Beta strand

305 – 307

3

Beta strand

310 – 313

4

Beta strand

318 – 320

3

Helix

321 – 330

10

Beta strand

335 – 337

3

Beta strand

338 – 342

5

Sequences

	Sequence		Length	Mass (Da)
	Q03526 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: F7A4A18A8A1AADDC	FASTA	625	72,292
	10 20 30 40 50 60 MNNFILLEEQ LIKKSQQKRR TSPSNFKVRF FVLTKASLAY FEDRHGKKRT LKGSIELSRI 70 80 90 100 110 120 KCVEIVKSDI SIPCHYKYPF QTLVYLQVVH DNYLLYVFAP DCESRQRWVL TLKEETRNNN 130 140 150 160 170 180 SLVSKYHPNF WMDGRWRCCS QLEKPAVGCA PYDPSKNASK KPLPPTPEDN RRSFQEPEET 190 200 210 220 230 240 LVIALYDYQT NDPQELALRC DEEYYLLDSS EIHWWRVQDK NGHEGYAPSS YLVEKSPNNL 250 260 270 280 290 300 ETYEWYNKSI SRDKAEKLLL DTGKEGAFMV RDSRTPGTYT VSVFTKAIIS ENPCIKHYHI 310 320 330 340 350 360 KETNDSPKRY YVAEKYVFDS IPLLIQYHQY NGGGLVTRLR YPVCSWRQKA PVTAGLRYGK 370 380 390 400 410 420 WVIQPSELTF VQEIGSGQFG LVHLGYWLNK DKVAIKTIQE GAMSEEDFIE EAEVMMKLSH 430 440 450 460 470 480 PKLVQLYGVC LEQAPICLVF EFMEHGCLSD YLRSQRGLFA AETLLGMCLD VCEGMAYLEK 490 500 510 520 530 540 ACVIHRDLAA RNCLVGENQV IKVSDFGMTR FVLDDQYTSS TGTKFPVKWA SPEVFSFSRY 550 560 570 580 590 600 SSKSDVWSFG VLMWEVFSEG KIPYENRSNS EVVEDISTGF RLYKPRLASC HVYQIMNHCW 610 620 KEKPEDRPPF SQLLSQLAEI AEAGL

References

[1]	"itk, a T-cell-specific tyrosine kinase gene inducible by interleukin 2." Siliciano J.D., Morrow T.A., Desiderio S.V. Proc. Natl. Acad. Sci. U.S.A. 89:11194-11198(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Thymocyte.
[2]	"Developmental regulation of a murine T-cell-specific tyrosine kinase gene, Tsk." Heyeck S.D., Berg L.J. Proc. Natl. Acad. Sci. U.S.A. 90:669-673(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Thymocyte.
[3]	"Structure and expression of novel protein-tyrosine kinases, Emb and Emt, in hematopoietic cells." Yamada N., Kawakami Y., Kimura H., Fukamachi H., Baier G., Altman A., Kato T., Inagaki Y., Kawakami T. Biochem. Biophys. Res. Commun. 192:231-240(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: CBA/J. Tissue: Mast cell.
[4]	Ogata M., Sawada M., Fujiwara H., Hamaoka T. Submitted (JAN-1993) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk." Liao X.C., Littman D.R. Immunity 3:757-769(1995) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[6]	"Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling." Fu G., Vallee S., Rybakin V., McGuire M.V., Ampudia J., Brockmeyer C., Salek M., Fallen P.R., Hoerter J.A.H., Munshi A., Huang Y.H., Hu J., Fox H.S., Sauer K., Acuto O., Gascoigne N.R.J. Nat. Immunol. 10:848-856(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH THEMIS.
[7]	"Regulatory intramolecular association in a tyrosine kinase of the Tec family." Andreotti A.H., Bunnell S.C., Feng S., Berg L.J., Schreiber S.L. Nature 385:93-97(1997) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 160-236.
[8]	"CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line." August A., Gibson S., Kawakami Y., Kawakami T., Mills G.B., Dupont B. Proc. Natl. Acad. Sci. U.S.A. 91:9347-9351(1994) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[9]	"CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK." King P.D., Sadra A., Han A., Liu X.-R., Sunder-Plassmann R., Reinherz E.L., Dupont B. Int. Immunol. 8:1707-1714(1996) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[10]	"Emt/Itk associates with activated TCR complexes: role of the pleckstrin homology domain." Ching K.A., Kawakami Y., Kawakami T., Tsoukas C.D. J. Immunol. 163:6006-6013(1999) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[11]	"Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity." Schaeffer E.M., Debnath J., Yap G., McVicar D., Liao X.C., Littman D.R., Sher A., Varmus H.E., Lenardo M.J., Schwartzberg P.L. Science 284:638-641(1999) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[12]	"Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk." Broussard C., Fleischacker C., Horai R., Chetana M., Venegas A.M., Sharp L.L., Hedrick S.M., Fowlkes B.J., Schwartzberg P.L. Immunity 25:93-104(2006) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[13]	"Disrupting the intermolecular self-association of Itk enhances T cell signaling." Min L., Wu W., Joseph R.E., Fulton D.B., Berg L., Andreotti A.H. J. Immunol. 184:4228-4235(2010) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[14]	"Interleukin-2-inducible T cell kinase (Itk) network edge dependence for the maturation of iNKT cell." Qi Q., Xia M., Bai Y., Yu S., Cantorna M., August A. J. Biol. Chem. 286:138-146(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN INVARIANT NKT CELL MATURATION, DISRUPTION PHENOTYPE.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L00619 mRNA. Translation: AAA39337.1.
L05631 mRNA. Translation: AAA40518.1.
L10628 mRNA. No translation available.
D14042 mRNA. Translation: BAA03129.1.

IPI

IPI00133425.

PIR

A43030.

RefSeq

NP_034713.2. NM_010583.2.

UniGene

Mm.339927.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1AWJ	NMR	-	A	160-236	[»]
1LUI	NMR	-	A	238-344	[»]
1LUK	NMR	-	A	238-344	[»]
1LUM	NMR	-	A	238-344	[»]
1LUN	NMR	-	A	238-344	[»]
2ETZ	NMR	-	A	238-344	[»]
2EU0	NMR	-	A	238-344	[»]
2K79	NMR	-	A	177-237	[»]
			B	238-344	[»]
2K7A	NMR	-	A	177-237	[»]
			B	238-344	[»]
2RN8	NMR	-	A	177-238	[»]
2RNA	NMR	-	A	177-238	[»]
3S9K	X-ray	2.35	A	236-344	[»]

ProteinModelPortal

Q03526.

SMR

Q03526. Positions 5-623.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29283N.

IntAct

Q03526. 4 interactions.

MINT

MINT-84965.

PTM databases

PhosphoSite

Q03526.

Proteomic databases

PRIDE

Q03526.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000109237; ENSMUSP00000104860; ENSMUSG00000020395.

GeneID

16428.

KEGG

mmu:16428.

UCSC

uc011xtn.1. mouse.

Organism-specific databases

CTD

3702.

MGI

MGI:96621. Itk.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00640000091251.

HOGENOM

HOG000233859.

HOVERGEN

HBG008761.

InParanoid

Q03526.

KO

K07363.

OMA

HVYQIMN.

OrthoDB

EOG48WC1S.

Enzyme and pathway databases

BRENDA

2.7.10.1. 3474.

Gene expression databases

ArrayExpress

Q03526.

Bgee

Q03526.

CleanEx

MM_ITK.

Genevestigator

Q03526.

GermOnline

ENSMUSG00000020395. Mus musculus.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.
3.30.505.10. 1 hit.

InterPro

IPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR001562. Znf_Btk_motif.
[Graphical view]

Pfam

PF00779. BTK. 1 hit.
PF00169. PH. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

PRINTS

PR00401. SH2DOMAIN.
PR00402. TECBTKDOMAIN.
PR00109. TYRKINASE.

SMART

SM00107. BTK. 1 hit.
SM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.
SSF50044. SH3. 1 hit.

PROSITE

PS50003. PH_DOMAIN. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
PS51113. ZF_BTK. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q03526.

NextBio

289653.

SOURCE

Search...

Entry information

Entry name

ITK_MOUSE

Accession

Primary (citable) accession number: Q03526

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	May 29, 2013
This is version 141 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program